COVID-19 and Toll-Like Receptor 4 (TLR4): SARS-CoV-2 May Bind and Activate TLR4 to Increase ACE2 Expression, Facilitating Entry and Causing Hyperinflammation

Causes of mortality from COVID-19 include respiratory failure, heart failure, and sepsis/multiorgan failure. TLR4 is an innate immune receptor on the cell surface that recognizes pathogen-associated molecular patterns (PAMPs) including viral proteins and triggers the production of type I interferons and proinflammatory cytokines to combat infection. It is expressed on both immune cells and tissue-resident cells. ACE2, the reported entry receptor for SARS-CoV-2, is only present on ~1-2% of the cells in the lungs or has a low pulmonary expression, and recently, the spike protein has been proposed to have the strongest protein-protein interaction with TLR4. Here, we review and connect evidence for SARS-CoV-1 and SARS-CoV-2 having direct and indirect binding to TLR4, together with other viral precedents, which when combined shed light on the COVID-19 pathophysiological puzzle. We propose a model in which the SARS-CoV-2 spike glycoprotein binds TLR4 and activates TLR4 signalling to increase cell surface expression of ACE2 facilitating entry. SARS-CoV-2 also destroys the type II alveolar cells that secrete pulmonary surfactants, which normally decrease the air/tissue surface tension and block TLR4 in the lungs thus promoting ARDS and inflammation. Furthermore, SARS-CoV-2-induced myocarditis and multiple-organ injury may be due to TLR4 activation, aberrant TLR4 signalling, and hyperinflammation in COVID-19 patients. Therefore, TLR4 contributes significantly to the pathogenesis of SARS-CoV-2, and its overactivation causes a prolonged or excessive innate immune response. TLR4 appears to be a promising therapeutic target in COVID-19, and since TLR4 antagonists have been previously trialled in sepsis and in other antiviral contexts, we propose the clinical trial testing of TLR4 antagonists in the treatment of severe COVID-19. Also, ongoing clinical trials of pulmonary surfactants in COVID-19 hold promise since they also block TLR4.

A Meta-Analysis of the Effects and Safety of Pulmonary Surfactants Combined with Budesonide in Bronchopulmonary Dysplasia

Context: The purpose of this analysis was to explore the effects and safety of Pulmonary Surfactants (PS) combined with budesonide in Bronchopulmonary Dysplasia (BPD) by a meta-analysis of Randomized Controlled Trials (RCTs). Evidence acquisition: Literature searches were performed in PubMed, the Cochrane Library, EMBASE, the China Knowledge Network, and the Wanfang database to collect data from RCTs. The primary outcomes were BPD incidence and BPD-related mortality, while the secondary outcomes were BPD-related complications. Bias was evaluated by the Cochrane risk assessment tool. The RevMan 5.3 software was used for the meta-analysis, and the Egger’s test was used for publication bias assessment. Results: A total of 720 subjects were enrolled from six RCTs, including 352 in the experimental group and 368 in the observation group. The BPD incidence (RR = 0. 42, 95% CI [0. 37, 0. 89], P < 0.001) and BPD-related mortality (RR = 0.54, 95% CI [0.38, 0.89], P < 0.05) differed significantly between the two groups. Significant differences were also found in intraventricular hemorrhage, infection/sepsis, Retinopathy of Prematurity (ROP), and Patent Ductus Arteriosus (PDA). There were no significant differences in the incidence of PDA, Neonatal Necrotizing Enterocolitis (NEC), hyperglycemia, and hypertension. Conclusions: The intratracheal instillation of pulmonary surfactants with budesonide can reduce the incidence of BPD and BPD-related mortality with no increased risk of short-term complications.

Meta-analysis of the efficacy of pulmonary surfactants combined with budesonide for the prevention of bronchopulmonary dysplasia

Background Pulmonary surfactants(PS) combined with the intratracheal instillation of budesonide to prevent bronchopulmonary dysplasia (BPD) have been report previously. However, the safety of the use of PS combined with budesonide is still unknown and remains to be clarified. Methods PubMed, the CochraneLibrary, EMBASE, the China Knowledge Network and the Wanfang database were searched for relevant studies. Searches were performed from December 2018, and data from randomized controlled trials (RCTs) were collected. Primary outcome measures were BPD incidence, BPD-related mortality. Secondary outcomes were BPD-related complications. The Cochrane risk assessment tool was used for the evaluation of bias. RevMan5. 3software was employed for meta-analysis. An Egger's test was used for publication bias assessments. Results A total of 720 subjects were enrolled from 6 RCTs, including 352 in the experimental group and 368 in the observation group. A meta-analysis showed that the incidence of BPD [RR=0. 42, 95% CI (0. 37, 0. 89), P < 0.001] and BPD-related mortality [RR = 0.54, 95% CI (0.38, 0.89), P<0.05] significantly differed between the groups. Differences were also observed for intraventricular hemorrhage, infection/sepsis, retinopathy of prematurity (ROP), and patent ductus arteriosus. There were no significant differences in the incidence of PDA, neonatal necrotizing enterocolitis (NEC), hyperglycemia, or hypertension (P > 0.05). Conclusion The intratracheal instillation of pulmonary surfactants with budesonide can reduce the incidence of BPD and BPD-related mortality, with no increased risk of short-term complications. However, considering both sample size and study bias, the safety and efficacy of this treatment plan requires clarification in large-samples, and multi-center clinical RCTs. In addition, the impact of long-term complications such as neurodevelopmental disorders requires further assessment.

Pulmonary Surfactant Preparations and Surfactant Therapy for ARDS in Surgical Intensive Care (a Literature Review)

Introduction. Despite the fact that clinical studies of pulmonary surfactants conducted over many years have demonstrated their efficacy for the treatment of acute respiratory distress syndrome (ARDS) which led to their approval for use inRussia andBelarus, only a few similar positive results have been achieved in other countries. This calls for an extensive literature review for intensive care professionals.Materials and methods. Using the data from 87 papers this review covers the composition, properties, methods of administration and delivery strategies of surfactant in the treatment and prevention of ARDS in patients with sepsis, severe complex injuries, inhalation injuries and a range of complications associated with thoracic and cardiovascular surgical procedures, massive blood transfusions, severe obstetric pathologies and the A/H1N1 pneumonia.Results. The early administration of natural pulmonary surfactants within 24 hours following the onset of ARDS as a part of the ARDS combination treatment or prevention drives down the time on mechanical ventilation to six days or shorter, prevents ventilator-associated and hospital-acquired pneumonias, bringing the respiratory failure mortality rate down to 15–20%.Discussion. Offering the first attempt to discuss the causes of failure of Phase III multicenter clinical trials outsideRussia andBelarus, this review outlines recent developments in synthetic and powdered pulmonary surfactant preparations.Conclusion. Pulmonary surfactants are highly effective as a part of complex therapy in ARDS treatment and prevention, resulting in two to four fold drop in ARDS mortality rate. The timing of administration is seen as the key factor of the efficacy of surfactant therapy, explaining the differences in clinical trials results from different countries.